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8178578 Chemical compounds
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Inventor: Wallace, et al.
Date Issued: May 15, 2012
Application: 12/520,372
Filed: December 19, 2007
Inventors: Wallace; Timothy William (Stockport, GB)
Edwards; David John (Manchester, GB)
Hadfield; John Anthony (Cheshire, GB)
Assignee: The University of Manchester (Manchester, GB)
Primary Examiner: Dentz; Bernard
Assistant Examiner:
Attorney Or Agent: Michael Best & Friedrich LLP
U.S. Class: 514/450; 514/100; 549/213; 549/220; 549/354
Field Of Search: 549/354; 549/220; 514/450; 514/100
International Class: A61K 31/33; C07D 313/10; C07D 493/04; A61K 31/357
U.S Patent Documents:
Foreign Patent Documents:
Other References: United Kingdom Search Report for Application No. GB0625371.0 dated Apr. 18, 2007 (1 page). cited by other.
Galbraith et al., Combretastatin A4 Phosphate has tumor Antivascular Activity in Rat and Man as Demonstrated by Dynamic Magnetic Resonance Imaging, Journal of Clinical Oncology, Aug. 1, 2003, pp. 2831-2842, vol. 21, No. 15, American Society ofClinical Oncology. cited by other.
Galbraith et al., Effects of Combretatstatin A4 Phosphate on Endothelial Cell Morphology in Vitro and Relationship in Tumour Vascular Targeting Activity in Vivo, Anticancer Research, 2001, pp. 93-102, vol. 21, supplied by The British Library. citedby other.
Tozer, Measuring tumour vascular response to antivascular and antiangiogenic drugs, The British Journal of Radiology, Special Issue 2003, pp. S23-S35, vol. 76, The British Institute of Radiology. cited by other.
Grosios et al., In vivo and in vitro evaluation of combretatstatin A-4 and its sodium phosphate prodrug, British Journal of Cancer, 1999, pp. 1318-1327, vol. 81, No. 8, Cancer Research Campaign. cited by other.
Kochetkov et al., Schizandrin-Lignan of Unusual Structure, Tetrahedron Letters, 1961, pp. 730-734, No. 20, Pergamon Press Ltd., Great Britain, supplied by The British Library. cited by other.
Insole, Buttressing and Electronic Effects of meta- and para-Methoxy Substituents on the Configurational Stability of 5,7-Dihydro-1,11-dimethoxydibenz[c,e]oxepine, Journal of Chemical Research (S), 1990, pp. 378-379, vol. 12, supplied by The BritishLibrary. cited by other.
Takada et al., Oxidative Biaryl Coupling Reaction of Phenol Ether Derivatives Using a Hypervalent Iodine(III) Reagent, Journal of Organic Chemistry, 1998, pp. 7698-7706, vol. 63, supplied by The British Library. cited by other.
Linden et al., (P,M)-1,2,3,9,10,11-Hexamethoxy-5,7-dihydrodibenz[c,e]oxepine and (P,M)-1,11-dimethyl-5,5,7,7-tetra-phenyl-5,7-dihydrodibenz[c,e]oxepine, Acta Crystallographica Section C, Crystal Structure Communications, 2004, pp. 223-225, vol. 60,International Union of Crystallography, supplied by The British Library. cited by other.
Edwards et al., Fine-tuning of biaryl dihedral angels: structural characterization of five homologous three-atom bridged biphenyls by X-ray crystallography, Acta Crystallographica Section B, Structural Science, 2005, pp. 335-345, vol. B61,International Union of Crystallography, Great Britain, supplied by The British Library. cited by other.
International Search Report from PCT/GB2007/004890 dated Aug. 13, 2008 (7 pages). cited by other.
Written Opinion from PCT/GB2007/004890 dated Aug. 13, 2008 (9 pages). cited by other.
Abe, H., et al.: "Enantioselective Construction of Biaryl Part in the Synthesis of Stegane Related Compounds", Tetrahedron Letters, vol. 45, (2004), pp. 2327-2329. cited by other.
Yoshiki Kashiwada, et al.: "New Hexahydroxybiphenyl Derivatives as Inhibitors of Protein Kinase C", Journal of Medicinal Chemistry, vol. 37, (1994), pp. 195-200. cited by other.
Buttner, F., et al.: "Two Novel Series of Allocolchicinoids with Modified Seven Membered B-Rings: Design, Synthesis, Inhibition of Tubulin Assembly and Cytotoxicity", Bioorganic & Medicinal Chemistry, vol. 13, (2005), pp. 3497-3511. cited by other.
Joncour, "Biaryl Axis as a Stereochemical Relay for the Enantioselective Synthesis of a Antimicrotubule Agents", Angew. Chem. Int. Ed., (2006), vol. 45, pp. 4149-4152. cited by other.









Abstract: A compound of formula (I) is described; wherein the substituents are as defined in the text and wherein the compound is intended for use in the production of a vascular damaging effect in a warm-blooded animal. ##STR00001##
Claim: The invention claimed is:

1. A method for producing a vascular damaging effect in a warm-blooded animal comprising administering to a warm-blooded animal in need thereof an effective amount of acompound represented by Formula I: ##STR00030## or a pharmaceutically acceptable salt thereof wherein: R.sup.1, R.sup.2 and R.sup.3 each independently represent (1-4C)alkoxy; Q.sup.1, Q.sup.2, Q.sup.3 and Q.sup.4 each independently represent hydrogen,halogeno, hydroxy, cyano, nitro, trifluoromethyl, thiol, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, (1-4C)alkylthio, (1-4C)alkylsulfonyl, (1-4C)alkylsulfonyloxy, an alkali metal phosphatogroup, or a group of the formula: NR.sup.4--C(O)--[C(R.sup.5)(N{R.sup.6}.sub.3.sup.+(X.sup.n-).sub.1/n]--C(- R.sup.7).sub.2(OH) wherein R.sup.4, R.sup.5, R.sup.6 and R.sup.7 each independently represent hydrogen, (1-4C)alkyl, (2-4C)alkenyl or(2-4C)alkynyl, X.sup.n- represents a suitable anion and n is 1 or 2, or a group of the formula: --BR.sup.8R.sup.9 wherein R.sup.8 and R.sup.9 each independently represent hydrogen, hydroxy or (1-4C)alkoxy, or any one of Q.sup.2 and Q.sup.3 or Q.sup.3 andQ.sup.4 represents a methylenedioxy group; and wherein any CH.sub.2 or CH.sub.3 group within a R.sup.1, R.sup.2, R.sup.3, Q.sup.1, Q.sup.2, Q.sup.3 and/or Q.sup.4 substituent optionally bears on each said CH.sub.2 or CH.sub.3 group one or more halogenoor hydroxy substituents, provided that when Q.sup.1 represents hydrogen or methoxy and Q.sup.4 represents hydrogen, then Q.sup.2 and Q.sup.3 do not both represent methoxy.

2. The method of claim 1, wherein: Q.sup.1, Q.sup.2, Q.sup.3 and Q.sup.4 each independently represent hydrogen, halogeno, hydroxy, cyano, nitro, trifluoromethyl, thiol, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, amino,(1-4C)alkylamino, di-[(1-4C)alkyl]amino, (1-4C)alkylthio, (1-4C)alkylsulfonyl, an alkali metal phosphato group, or a group of the formula: --NR.sup.4--C(O)--[C(R.sup.5)(N{R.sup.6}.sub.3.sup.+(X.sup.n-).sub.1/n]--- C(R.sup.7).sub.2(OH) wherein R.sup.4,R.sup.5, R.sup.6 and R.sup.7 each independently represent hydrogen, (1-4C)alkyl, (2-4C)alkenyl or (2-4C)alkynyl, X.sup.n- represents a suitable anion and n is 1 or 2, or a group of the formula: --BR.sup.8R.sup.9 wherein R.sup.8 and R.sup.9 eachindependently represent hydrogen, hydroxy or (1-4C)alkoxy, or any one of Q.sup.2 and Q.sup.3 or Q.sup.3 and Q.sup.4 represents a methylenedioxy group; and wherein any CH.sub.2 or CH.sub.3 group within a R.sup.1, R.sup.2, R.sup.3, Q.sup.1, Q.sup.2,Q.sup.3 and/or Q.sup.4 substituent optionally bears on each said CH.sub.2 or CH.sub.3 group one or more halogeno or hydroxy substituents.

3. The method of claim 1, wherein: Q.sup.1, Q.sup.2, Q.sup.3 and Q.sup.4 each independently represent hydrogen, halogeno, hydroxy, cyano, nitro, trifluoromethyl, thiol, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, amino,(1-4C)alkylamino, di-[(1-4C)alkyl]amino, (1-4C)alkylthio, (1-4C)alkylsulfonyl, (1-4C)alkylsulfonyloxy, an alkali metal phosphato group, or a group of the formula: --NR.sup.4--C(O)--[C(R.sup.5)(N{R.sup.6}.sub.3.sup.+(X.sup.n-1).sub.1/n]---C(R.sup.7).sub.2(OH) wherein R.sup.4, R.sup.5, R.sup.6 and R.sup.7 each independently represent hydrogen, (1-4C)alkyl, (2-4C)alkenyl or (2-4C)alkynyl, X.sup.n- represents a suitable anion and n is 1 or 2, or a group of the formula: --BR.sup.8R.sup.9wherein R.sup.8 and R.sup.9 each independently represent hydrogen, hydroxy or (1-4C)alkoxy, or and wherein any CH.sub.2 or CH.sub.3 group within a R.sup.1, R.sup.2, R.sup.3, Q.sup.1, Q.sup.2, Q.sup.3 and/or Q.sup.4 substituent optionally bears on eachsaid CH.sub.2 or CH.sub.3 group one or more halogeno or hydroxy substituents.

4. The method of claim 1, wherein the vascular damaging effect is produced at least in part by inhibition of tubulin assembly into microtubules thereby interfering with cellular tubulin-microtubule equilibrium.

5. The method of claim 1, further comprising treating a disease or medical condition in which the damage of the vasculature in a warm-blooded animal has an effect.

6. The method of claim 1, further comprising treating a vascular proliferative disease or medical condition in a warm-blooded animal.

7. The method of claim 5, wherein the disease or medical condition is selected from one or more of a cancer, macular degeneration, proliferative retinopathy, psoriasis and/or endometriosis.

8. The method of claim 7, wherein the disease or medical condition is selected from a cancer, macular degeneration and/or proliferative retinopathy.

9. The method of claim 8, wherein the disease or medical condition is a cancer.

10. The method of claim 9, wherein the cancer is selected from one or more of leukaemias, colorectal, cervical, head and neck, lung, ovarian, pancreatic, thyroid, prostate, bladder, brain, breast, liver, stomach, oesophageal and/or skincancers.

11. The method of claim 9, wherein the disease or medical condition is a cancer involving a solid tumour.

12. The method of claim 11, wherein the cancer is selected from one or more of colorectal, cervical, head and neck, lung, ovarian, pancreatic, thyroid, prostate, bladder, brain, breast, liver, stomach, oesophageal and/or skin cancers.

13. The method of claim 7, wherein the disease or medical condition is macular degeneration.

14. A compound represented by Formula I: ##STR00031## or a pharmaceutically acceptable salt thereof wherein: R.sup.1, R.sup.2 and R.sup.3 each independently represent (1-4C)alkoxy; Q.sup.1, Q.sup.2, Q.sup.3 and Q.sup.4 each independentlyrepresent hydrogen, halogeno, hydroxy, cyano, nitro, trifluoromethyl, thiol, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, (1-4C)alkylthio, (1-4C)alkylsulfonyl, (1-4C)alkylsulfonyloxy, an alkalimetal phosphato group, or a group of the formula: --NR.sup.4--C(O)--[C(R.sup.5)(N{R.sup.6}.sub.3.sup.+(X.sup.n-).sub.1/n]--- C(R.sup.7).sub.2(OH) wherein R.sup.4, R.sup.5, R.sup.6 and R.sup.7 each independently represent hydrogen, (1-4C)alkyl,(2-4C)alkenyl or (2-4C)alkynyl, X.sup.n- represents a suitable anion and n is 1 or 2, or a group of the formula: --BR.sup.8R.sup.9 wherein R.sup.8 and R.sup.9 each independently represent hydrogen, hydroxy or (1-4C)alkoxy, or any one of Q.sup.2 andQ.sup.3 or Q.sup.3 and Q.sup.4 represents a methylenedioxy group; and wherein any CH.sub.2 or CH.sub.3 group within a R.sup.1, R.sup.2, R.sup.3, Q.sup.1, Q.sup.2, Q.sup.3 and/or Q.sup.4 substituent optionally bears on each said CH.sub.2 or CH.sub.3group one or more halogeno or hydroxy substituents; provided that when Q.sup.1 represents hydrogen or methoxy and Q.sup.4 represents hydrogen, then Q.sup.2 and Q.sup.3 do not both represent methoxy.

15. The compound of claim 14, wherein: Q.sup.1, Q.sup.2, Q.sup.3 and Q.sup.4 each independently represent hydrogen, halogeno, hydroxy, cyano, nitro, trifluoromethyl, thiol, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, amino,(1-4C)alkylamino, di-[(1-4C)alkyl]amino, (1-4C)alkylthio, (1-4C)alkylsulfonyl, an alkali metal phosphato group, or a group of the formula: --NR.sup.4--C(O)--[C(R.sup.5)(N{R.sup.6}.sub.3.sup.+(X.sup.n-).sub.1/n]--- C(R.sup.7).sub.2(OH) wherein R.sup.4,R.sup.5, R.sup.6 and R.sup.7 each independently represent hydrogen, (1-4C)alkyl, (2-4C)alkenyl or (2-4C)alkynyl, X.sup.n- represents a suitable anion and n is 1 or 2, or a group of the formula: --BR.sup.8R.sup.9 wherein R.sup.8 and R.sup.9 eachindependently represent hydrogen, hydroxy or (1-4C)alkoxy, or any one of Q.sup.2 and Q.sup.3 or Q.sup.3 and Q.sup.4 represents a methylenedioxy group; and wherein any CH.sub.2 or CH.sub.3 group within a Q.sup.1, Q.sup.2, Q.sup.3 and/or Q.sup.4substituent optionally bears on each said CH.sub.2 or CH.sub.3 group one or more halogeno or hydroxy substituents; provided that when Q.sup.1 represents hydrogen or methoxy and Q.sup.4 represents hydrogen, then Q.sup.2 and Q.sup.3 do not both representmethoxy.

16. The compound of claim 14, wherein: Q.sup.1, Q.sup.2, Q.sup.3 and Q.sup.4 each independently represent hydrogen, halogeno, hydroxy, thiol, (2-4C)alkynyl, (1-4C)alkoxy, amino, (1-4C)alkylsulfonyloxy, an alkali metal phosphato group, or agroup of the formula: --BR.sup.8R.sup.9 wherein R.sup.8 and R.sup.9 each independently represent hydrogen, hydroxy or (1-4C)alkoxy, and wherein any CH.sub.2 or CH.sub.3 group within a Q.sup.1, Q.sup.2, Q.sup.3 and/or Q.sup.4 substituent optionally bearson each said CH.sub.2 or CH.sub.3 group one or more halogeno or hydroxy substituents; provided that when Q.sup.1 represents hydrogen or methoxy and Q.sup.4 represents hydrogen, then Q.sup.2 and Q.sup.3 do not both represent methoxy.

17. The compound of claim 14, wherein Q.sup.1 represents hydrogen.

18. The compound of claim 14, wherein Q.sup.4 does not represent hydrogen.

19. The compound of claim 14, wherein the compound is represented by Formula I'': ##STR00032## or a pharmaceutically acceptable salt thereof wherein: R.sup.1, R.sup.2 and R.sup.3 each independently represent (1-4C)alkoxy; Q.sup.3 and Q.sup.4each independently represent halogeno, hydroxy, cyano, nitro, trifluoromethyl, thiol, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, (1-4C)alkylthio, (1-4C)alkylsulfonyl, (1-4C)alkylsulfonyloxy,an alkali metal phosphato group, or a group of the formula: NR.sup.4--C(O)--[C(R.sup.5)(N{R.sup.6}.sub.3.sup.+(X.sup.n-).sub.1/n]--C(- R.sup.7).sub.2(OH) wherein R.sup.4, R.sup.5, R.sup.6 and R.sup.7 each independently represent hydrogen, (1-4C)alkyl,(2-4C)alkenyl or (2-4C)alkynyl, X.sup.n- represents a suitable anion and n is 1 or 2, or a group of the formula: --BR.sup.8R.sup.9 wherein R.sup.8 and R.sup.9 each independently represent hydrogen, hydroxy or (1-4C)alkoxy, or Q.sup.3 and Q.sup.4represent a methylenedioxy group; and wherein any CH.sub.2 or CH.sub.3 group within a R.sup.1, R.sup.2, R.sup.3, Q.sup.3 and/or Q.sup.4 substituent optionally bears on each said CH.sub.2 or CH.sub.3 group one or more halogeno or hydroxy substituents.

20. The compound of claim 19, wherein: Q.sup.3 and Q.sup.4 each independently represent halogeno, hydroxy, thiol, (2-4C)alkynyl, (1-4C)alkoxy, amino, (1-4C)alkylsulfonyloxy, an alkali metal phosphato group, or a group of the formula:--BR.sup.8R.sup.9 wherein R.sup.8 and R.sup.9 each independently represent hydrogen, hydroxy or (1-4C)alkoxy, and wherein any CH.sub.2 or CH.sub.3 group within a Q.sup.3 and/or Q.sup.4 substituent optionally bears on each said CH.sub.2 or CH.sub.3 groupone or more halogeno or hydroxy substituents.

21. The compound of claim 14, wherein the compound is represented by Formula I''': ##STR00033## or a pharmaceutically acceptable salt thereof wherein: R.sup.1, R.sup.2 and R.sup.3 each independently represent (1-4C)alkoxy; Q.sup.2, Q.sup.3 andQ.sup.4 each independently represent halogeno, hydroxy, cyano, nitro, trifluoromethyl, thiol, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, (1-4C)alkylthio, (1-4C)alkylsulfonyl,(1-4C)alkylsulfonyloxy, an alkali metal phosphato group, or a group of the formula: --NR.sup.4--C(O)--[C(R.sup.5)(N{R.sup.6}.sub.3.sup.+(X.sup.n-).sub.1/n]--- C(R.sup.7).sub.2(OH) wherein R.sup.4, R.sup.5, R.sup.6 and R.sup.7 each independently representhydrogen, (1-4C)alkyl, (2-4C)alkenyl or (2-4C)alkynyl, X.sup.n- represents a suitable anion and n is 1 or 2, or a group of the formula: --BR.sup.8R.sup.9 wherein R.sup.8 and R.sup.9 each independently represent hydrogen, hydroxy or (1-4C)alkoxy, or anyone of Q.sup.2 and Q.sup.3 or Q.sup.3 and Q.sup.4 represents a methylenedioxy group; and wherein any CH.sub.2 or CH.sub.3 group within a R.sup.1, R.sup.2, R.sup.3, Q.sup.2, Q.sup.3 and/or Q.sup.4 substituent optionally bears on each said CH.sub.2 orCH.sub.3 group one or more halogeno or hydroxy substituents.

22. The compound of claim 21, wherein: Q.sup.2, Q.sup.3 and Q.sup.4 each independently represent halogeno, hydroxy, thiol, (2-4C)alkynyl, (1-4C)alkoxy, amino, (1-4C)alkylsulfonyloxy, an alkali metal phosphato group, or a group of the formula:--BR.sup.8R.sup.9 wherein R.sup.8 and R.sup.9 each independently represent hydrogen, hydroxy or (1-4C)alkoxy, and wherein any CH.sub.2 or CH.sub.3 group within a Q.sup.2, Q.sup.3 and/or Q.sup.4 substituent optionally bears on each said CH.sub.2 orCH.sub.3 group one or more halogeno or hydroxy substituents.

23. The compound of claim 14, wherein R.sup.1, R.sup.2 and R.sup.3 each independently represent (1-2C)alkoxy.

24. The compound of claim 23, wherein R.sup.1, R.sup.2 and R.sup.3 each represent methoxy.

25. A compound of claim 14, selected from one or more of the following: 1,2,3,9-tetramethoxy-5,7-dihydrodibenzo[c,e]oxepine; 5,7-dihydro-1,2,3-trimethoxybenzo[d][1,3]dioxolo[4,5-h][2]benzoxepin; 3,9,10,11-tetramethoxy-5,7-dihydrodibenzo[c,e]oxepin-4-ol; 3,9,10,11-tetramethoxy-5,7-dihydrodibenzo[c,e]oxepin-4-yl disodium phosphate; 1,2,3-trimethoxy-9-nitro-5,7-dihydrodibenzo[c,e]oxepine; 9,10,11-trimethoxy-5,7-dihydrodibenzo[c,e]oxepin-3-amine; 3,9,10,11-tetramethoxy-5,7-dihydrodibenzo[c,e]oxepin-4-yl trifluoromethanesulfonate; 3,9,10,11-tetramethoxy-5,7-dihydrodibenzo[c,e]oxepine-4-thiol; and 3,9,10,11-tetramethoxy-5,7-dihydrodibenzo[c,e]oxepin-4-amine; or a pharmaceutically acceptable saltthereof.

26. A method for the preparation of a compound of claim 14 or a pharmaceutically acceptable salt thereof, the method comprising reacting a compound represented by Formula II: ##STR00034## wherein R.sup.1, R.sup.2, R.sup.3, Q.sup.1, Q.sup.2,Q.sup.3 and Q.sup.4 have any of the meanings defined in claim 14 except that any functional group is protected if necessary and L.sup.1 is a suitable displaceable group, with a suitable ring closure reagent; and optionally, (i) converting a compoundrepresented by Formula I into another compound represented by Formula I; and/or (ii) removing any protecting group that is present; and/or (iii) forming a pharmaceutically acceptable salt.

27. A pharmaceutical composition comprising: a compound of claim 14 or a pharmaceutically acceptable salt thereof; and (B) a pharmaceutically acceptable adjuvant, diluent or carrier.

28. The composition of claim 27, further comprising an additional anti-tumour agent for the conjoint treatment of a cancer.
Description:
 
 
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